Effect of patient inhalation profile and airway structure on drug deposition in image-based models with particle-particle interactions

Metered Dose Inhalers are a commonly prescribed delivery method for prescription medications in primary care that have been demonstrated to have poor rates of proper technique by patients, especially in kids which results in less effective inhalation outcomes. The effectiveness of inhaled drug is related to the amount of drug deposited beyond the oropharyngeal region. It is usually also important to consider the size of the inhaled particles, the breathing conditions, the geometry of the airways and the mucus clearance mechanisms. Currently, mathematical models are being applied to describe the deposition of inhaled drugs based on the size of the particles, the inspiratory flow and the anatomical distribution of the bronchial tree. The deposition of particles in the small airways gets maximum attention from pharmaceutical companies developing treatments for asthma and cystic fibrosis and is of great interest as it is related with a better control in patients receiving these drugs. By providing clinicians with information on local deposition and therapeutic outcome, in silico analysis could be used to optimize drug deposition. Various 1D models exist to model deposition in airway trees, based on the airway diameter. However, complex fluid processes generated in the upper airways and particle interactions cannot be incorporated into these 1D airway representations.

In a previous study, sinusoidal inhalation profile was used which mimics a healthy patient’s tidal breathing. Different breathing profiles were used, to illustrate usual techniques for different devices (dry powder versus metered-dose inhalers). Limiting models to solely inhalation profiles reflective of healthy tidal breathing may result in inaccurate predictions of deposition due to the quicker and nonconstant flow created by a patient with breathing issues while inhaling.

In a new study published in International Journal of Pharmaceutics Mr. Josh Williams, Dr. Ali Ozel and Dr. Uwe Wolfram at Heriot-Watt University investigated the effect of patient-specific airway shape on drug deposition and effect of inhalation profile on drug deposition were evaluated. Dr. Jari Kolehmainen at Princeton University and Prof. Steve Cunningham from the University of Edinburgh were also co-authors and contributed to the study.

The research team found that patient-specific domains are required in future studies after exploring this in a small, diverse patient sample. There was a considerable variation in upper airway deposition with airway shape and breathing profile for large particles (10 μm). For all airway shapes and breathing profiles, small particles (4 μm) showed less sensitivity to total upper airway deposition. This demonstrates that tiny particles are best for enhancing drug penetration into the deep lung when breathing is impaired by disease. The transition from a fast-flowing, constricted throat to an expanding and curved trachea in cystic fibrosis and cancer patients result in noticeable differences in trachea deposition. This is consistent with single-phase simulations, which demonstrated that flow varies with orientation and that pathological trachea curvature affects gas pressure and energy loss. Alterations in the trachea’s relative orientation to gravity are also a contributing element to deposition changes.

Changes in the trachea’s relative orientation to gravity are another element that affects deposition. Deposition hotspots are formed by healthy breathing, mainly at the bifurcation points. This happens because the effect of particle drift towards the tracheal wall (turbophoresis) is inherently reduced in a lower Reynolds number flow, causing particles to settle primarily at bifurcation sites due to inertial impact. During impaired breathing, however, the deposition of 4 μm particles was more equally scattered on the airway wall than during a healthy inhalation.

To achieve a balanced dosage distribution or to target a specific region, patient-specific models could be employed. This could lead to better symptom alleviation by allowing inhaler design to be influenced by knowledge of regions sensitive to local inflammation, resulting in more efficient devices. Additionally, nebulizers could be used to target malignant lung regions for chemotherapy. In their paper, the authors reported few limitations of their study, for example, the absence of CT data for the child’s throat and mouth, implying that this region was calculated from other patient populations. The specificity of the principal deposition location is, of course, limited as a result.

In summary, successful pulmonary drug delivery presents many challenges, but interest in the pulmonary route seems to be greater than ever. In order to optimize delivery of inhaled drugs for systemic effect, companies have sought to maximize lung deposition via design of the inhaler device or formulation. According to the authors, respiratory computational particle–fluid dynamics (CPFD) trials, image-based models are also required to predict a better treatment outcome. In order to optimize patient therapies, image-based models should be integrated with inhalation profiles that depict various respiratory limitations, such as recovering from an exacerbation, downstream airway blockage, or mucus plugging.